TPMT genetic variants are associated with increased rejection with azathioprine use in heart transplantation

Jackson J. Liang, Jennifer R. Geske, Barry A. Boilson, Robert P. Frantz, Brooks S. Edwards, Sudhir S. Kushwaha, Walter K. Kremers, Richard M. Weinshilboum, Naveen L. Pereira

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Objectives Azathioprine (AZA) is an important immunosuppressant drug used in heart transplantation (HTX). Consensus guidelines recommend that patients with thiopurine S-methyltransferase (TPMT) genetic variants be started on lower AZA dose because of higher active metabolite levels and risk of adverse events. However, in-vitro lymphocyte proliferation assays performed in participants with inactive TPMT alleles have suggested that AZA use may result in decreased immunosuppressant efficacy as compared with wild-type (WT) individuals. The objective of this study was therefore to determine the effect of TPMT genetic variation on AZA efficacy or prevention of rejection in HTX recipients treated with AZA. Participants and methods We genotyped 93 HTX recipients treated with AZA and measured erythrocyte TPMT enzyme activity. Acute rejection was monitored by routine endomyocardial biopsies. Results There were 83 WT and 10 heterozygote (HZ) HTX recipients. TPMT activity level was lower in HZ compared with WT (13.1±2.8 vs. 21±4.5 U/ml red blood cell, P< 0.001). Despite similar AZA dose, HZ developed severe rejection earlier (P< 0.001), and the total rejection score was higher (P = 0.02) than WT. AZA was discontinued more frequently in HZ (P = 0.01) because of rejection. The incidence of leukopenia was similar between the groups (40 vs. 43%, P =1.0). Conclusion HTX recipients with TPMT genetic variant alleles who are treated with AZA develop acute rejection earlier, more frequently, and of greater severity. These patients, despite having lower TPMT enzymatic activity, should be monitored carefully for possible increased risk of acute rejection. Pharmacogenetics and Genomics 23:658-665

Original languageEnglish (US)
Pages (from-to)658-665
Number of pages8
JournalPharmacogenetics and genomics
Volume23
Issue number12
DOIs
StatePublished - Dec 2013

Keywords

  • Azathioprine
  • Heart transplantation
  • Pharmacogenomics
  • Rejection
  • Thiopurine S-methyltransferase
  • Toxicity

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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